Memorandum

J&J’s Invokana receives CV indication in EU – September 10, 2018

Executive Highlights

  • The European Commission approved an updated indication for J&J’s SGLT-2 inhibitor Invokana. Data from the CANVAS CVOT reflecting a reduction in three-point MACE with Invokana, in people with type 2 diabetes and CVD or high CV risk, will be added to the product label. According to European distribution partner Mundipharma, data on hospitalization for heart failure and renal outcomes will also be added to the label. The EU label for Lilly/BI’s Jardiance contains equivalent data from EMPA-REG OUTCOME

  • We’re optimistic that this update, and hopefully an indication in the US, could aid the pressured Invokana franchise. Following the amputation risk associated with Invokana in CANVAS (HR=1.97, 95% CI: 1.41-2.75), the franchise has struggled commercially, posting six consecutive quarters of YOY decline as of 2Q18. A formal indication should help bring attention to the meaningful CV benefits Invokana offers. We continue to agree with thought leaders that this degree of amputation risk is manageable with patient selection and patient/provider education, and we’re also highly positive about the emerging renal benefits of SGLT-2s. We are very surprised not to see J&J offer more support to this important franchise.

  • Following a three-month delay, a decision from FDA on the US label is now expected by the end of October 2018. FDA requested additional analyses from J&J, and we note that the agency also delayed its decision on Jardiance’s CV indication. We remain curious what indication FDA is considering for Invokana: Jardiance holds an indication for reduction of CV death, but Invokana did not demonstrate benefit on this endpoint alone in CANVAS. Will Invokana become the first SGLT-2 to gain a MACE indication, despite nearly identical results on this endpoint as Jardiance?

    J&J’s SGLT-2 inhibitor Invokana (canagliflozin) has received a CV indication in the EU. On Friday, the European Commission approved an update to Invokana’s indication statement and the addition of CANVAS data to the drug’s product information. According to J&J, the label will now include information on Invokana’s effects on MACE in patients with type 2 diabetes and CVD or high CV risk. The change also applies to Vokanamet, the fixed-dose combination with metformin.

    This news follows a positive CHMP opinion on the label update in the EU (August 2018), subsequent to the company’s 3Q17 Type II Variation application to EMA based on results from the CANVAS CVOT, which was presented at ADA 2017.

    Somewhat surprisingly, we could not find a press release about this news on Janssen or J&J’s website. J&J’s partner Mundipharma, which distributes Invokana in most of Europe, did announce the decision.  

    Mundipharma’s announcement also references the addition of CANVAS data on hospitalization for heart failure and renal outcomes to the EU label. To our understanding, the online label for Invokana has yet to be updated with this approval, but we noted that the EU label for Lilly/BI’s Jardiance does also include data indicating benefit on both of these endpoints from EMPA-REG OUTCOME. In our assessment, then, EMA has granted Invokana an update equivalent to that given to Jardiance.

    • A CV indication in the EU – and hopefully in the US (more below) – could be a welcome tailwind for the Invokana franchise, which has been pressured in the face of safety concerns. Indeed, the announcement itself references the amputation signal associated with Invokana, as identified in CANVAS (HR=1.97, 95% CI: 1.41-2.75, p<0.001), as well as the class-wide warning for amputations that EMA has placed on all SGLT-2 inhibitors. Our observation is that concern over amputations among both patients and providers has hindered uptake of SGLT-2s, but Invokana has seen the most negative impact: From 2Q17 to 2Q18, Invokana’s value share of the global SGLT-2 market fell from ~34% to ~21%; in 2Q18, the franchise itself fell 27% YOY to $215 million. We’re optimistic that official recognition of Invokana’s CV benefit will translate to greater recognition of this highly-positive aspect of the therapy’s risk-benefit profile by making both efficacy and safety data more accessible to patients and HCPs. While some thought leaders have questioned the use of Invokana when other options have demonstrated CV protection without a signal for amputations, it’s not often the case that a patient has the option to choose between two SGLT-2 inhibitors, due to formulary restrictions. Moreover, a definite majority of thought leaders, in our observation, have argued that amputation risk is highly manageable with careful patient selection and diligent monitoring of the feet. Barriers to “best practices” for foot care in diabetes certainly exists, time being perhaps the most prominent, but this problem is solvable through HCP and patient education. There’s no doubt that more patients could be meaningfully benefitting from the reduction in major adverse CV events that SGLT-2 inhibitors offer, and our hope is that a CV indication can help Invokana and its fellow class members reach more people with diabetes.

      • Another critical boon for Invokana and the SGLT-2 class should come from J&J’s renal outcomes trial for Invokana, CREDENCE. In some of the most positive news we’ve heard in diabetes this year, CREDENCE was stopped early (July 2018) for meeting its primary endpoint ~1 year ahead of schedule, indicating very impressive efficacy on preventing the progression of CKD (primary endpoint components were end-stage renal disease, doubling of serum creatinine, and renal or CV death). While we still await the first topline data, we certainly expect another set of regulatory submissions for a renal indication from J&J – which would be an incredibly welcome addition to the treatment arsenal for diabetic kidney disease, given the depth of unmet need patients and providers face in treating renal disease. Results from Dapa-CKD and EMPA-KIDNEY, both of which are enrolling people with and without diabetes, are poised to solidify this benefit as a class effect (expected completion in November 2020 and June 2022, respectively).

    • In the US, FDA recently (July 2018) delayed its decision on J&J’s sNDA by three months, requesting additional analyses from the company. A decision is now expected by the end of October 2018; FDA also delayed its decision on Jardiance’s CV indication (August 2016). We remain very curious as to what precise indication FDA is considering for Invokana. In the US, Jardiance is indicated for the reduction of CV death in people with type 2 diabetes and CVD, while Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) is indicated more broadly for the reduction of MACE, in the same population. Our sense is that Jardiance received a narrower indication because the 14% risk reduction on three-point MACE (95% CI: 0.74-0.99) identified in EMPA-REG OUTCOME was driven by a 38% risk reduction on CV death (HR=0.62, 95% CI: 0.49-0.77). However, in CANVAS, no single MACE endpoint met significance on its own. It’s also possible that, due to the novelty of the indication, FDA took a more conservative stance. Our question remains: Has FDA become more open to granting SGLT-2s a full MACE indication, as with Victoza? Additionally, as weeks roll by it becomes less likely that FDA will convene an Ad Comm to discuss the indication, but we wouldn’t rule out the possibility, particularly given the amputation risk that has been associated with Invokana.

      • Some have suggested the evidence of Invokana’s CV benefit isn’t as robust as the evidence supporting Jardiance’s benefit. In a provocative presentation at CMHC West, Dr. Sanjay Kaul re-analyzed CANVAS using Bayesian statistics and argued that there is insufficient evidence of Invokana’s CV benefits, going so far as to say he “wouldn’t be surprised” if FDA denies the indication. Moreover, as we understand it, FDA uses a different and often more rigorous statistical methodology: At the Ad Comm for Jardiance’s CV indication (June 2016), FDA presented slightly different findings for EMPA-REG OUTCOME than were reported by Lilly/BI. On the other hand, our overwhelming sense from diabetes thought leaders is that cardioprotection is an SGLT-2 inhibitor class effect – of course, the two opinions aren’t mutually exclusive: A weakness in the evidence certainly doesn’t mean the benefit isn’t there. In our observation, the fields of both endocrinology and cardiology continue to see CANVAS as a very positive trial on cardio- and renal-protection, and we vehemently agree.

     

    --by Ann Carracher and Kelly Close